2-Fluoroadenine is an intermediate product for the preparation of 2-fluoroadenosine, an important antitumor agent.
It has been known for a long time that fluorine can be introduced through replacement of the amino group in aromatic or heterocyclic compounds via diazonium compounds [Methoden der Organischen Chemie; Houben-Weyl; Volume V/3 (1962); page 213ff].
For the diazotation a suitable nitrite, such as an organic alkyl nitrite, in particular a tertiary alkyl nitrite, like t-butyl nitrite, or an alkali metal nitrite, such as lithium, sodium or potassium nitrite is used. As fluorinating agents, hydrofluoric acid and hydrofluoric acid-amine complexes, such as pyridine-HF (Georges A. Olah; J. Org. Chemie (1979); 44; 3872ff) and tetrafluoroborate in the Schiemann reaction are used.
The reaction—diazotation with simultaneous fluorination—is carried out mainly under as anhydrous conditions as possible [Morris J. Robins, Bogdan Uznanski; Can. J. Chem (1981); 59; 2608].
Preferred methods are usually sodium nitrite in pyridine-hydrofluoric acid complex or in anhydrous hydrofluoric acid.
The selective introduction of fluorine through diazotation of 2,6-diaminopurine in the presence of a fluorinating agent according to Schiemann to give 2-fluoroadenine is already disclosed by J. A. Montgommery et al. in J. Amer. Chem. Soc. (1960); 82; 463 ff. The way for carrying out the reaction and the work-up therein disclosed are completely unacceptable for technical use. The yields are around 6% and the purity around 90%.
A slightly improved method, i.e. the reaction in anhydrous HF, with a slightly higher yield of 22%, is disclosed by Calley N. Eaton et al. in J. Org. Chem. (1969); 34; 747ff. The reaction—diazotation and fluorination—is carried out at 0° C. For the work-up, the residual HF is distilled off and after that the residue is first stirred with water. In order to reach the final purity of “analytically pure”, a further filtration on charcoal is carried out.
The selectivity of the introduction of fluorine in position 2 of 2-aminoadenosine is disclosed both on O-protected nucleosides by Morris J. Robins et al. in Can. J. Chem. (1981); 59; 2608ff, and by J. A. Montgomery in U.S. Pat. No. 4,188,378 and U.S. Pat. No. 4,210,745, and by H. Verbrüggen et al. in DE 4141454A1 on unprotected nucleosides.
If selective introduction of fluorine either on 2-aminoadenine or on 2-aminoadenosine, in protected or unprotected sugar portions, are carried out according to one of the available methods so far disclosed, the desired 2-fluoroadenine or 2-fluoroadenosine (O-protected or unprotected) can be obtained in poor yields only after difficult isolation from the reaction solution. Such work-up steps comprise mainly neutralisation of the reaction solution followed by extraction of the crude product from the reaction solution, or distillation of the HF in excess and suitable further purification of the obtained crude product.
According to the known methods, the further purification in order to reach the desired purity degree of at least 98% (HPLC Area), occurs only through further additional steps, such as column chromatography, purification on active charcoal or through recrystallization.